The proposed work is to engineer multiple independent invasive gene drive systems in the Dengue mosquito, Aedes aegypti, a major vector of human insect-borne disease known to annually infect 50-100 million people worldwide, killing millions. The current approaches used for Dengue disease prevention, including vector suppression by environmental modification, insecticides and anti-pathogen drugs are simply insufficient. The replacement of wild mosquito populations with genetically modified individuals that are engineered to be disease resistant in theory should provide a sustainable long-term method for disease prevention. However, the transgenes that mediate the disease refractoriness are unlikely to confer an overall fitness benefit on insects that carry them. Additionally, wild populations are large, partially reproductively isolated, and dispersed over wide areas. Therefore, population replacement requires a gene drive mechanism in order to spread linked cargo genes mediating disease refractoriness through wild populations. I have previously developed multiple synthetic selfish genetic elements including Maternal-Effect-Dominant-Embryonic-Arrest (Medea) and recently a threshold dependent underdominance system (UDmel) in insects that can rapidly spread through populations, even in the presence of a linked cargo refractory gene that may impose a large increase in fitness cost. Here I propose to simply transfer these synthetic systems into an insect that vectors disease, Aedes aegypti. Therefore, the major aims of this proposal are to develop three systems: 1) Medea, 2) Threshold dependent underdominance (UDmel), and 3) a selfish genetic element the can rapidly spread and crash a population, all in the Dengue vector, Aedes aegypti. Each of these gene drive systems have several attractive features important for social and scientific acceptance for wild transgene releases: the systems are species specific and horizontal spread with other species is limited; minimal ecological impact in contrast to insecticides; relatively robust and unbreakable with a tight linkage of the selfish genetic element with its cargo; transgene recall (for Medea) and complete transgene removal (underdominance) can be carried out if desired. In summary, the overall goal of this proposal is to develop multiple population control technologies in the mosquito that can be applied successfully and safely to fight human disease.